Khan_2025_Eur.J.Med.Chem_302_118371

Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which the decline of cholinergic neurotransmission plays a central role in cognitive impairment. Cholinesterase inhibition remains an established therapeutic approach to enhance acetylcholine levels and provide symptomatic relief. Natural alkaloids have long served as an important source of cholinesterase inhibitors, offering diverse molecular scaffolds, stereochemical complexity, and strong biological relevance. This review provides a comprehensive overview of natural alkaloids reported as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors, highlighting their structural diversity, mechanisms of inhibition, and structure-activity relationships. In addition, the review presents a brief analysis on the emerging pseudo-natural product (PNP) framework as a complementary strategy for designing new alkaloid-inspired potential inhibitors that combine nature-derived functionality with synthetic innovation. Overall, the manuscript underscores the enduring significance of alkaloids in cholinesterase inhibitor discovery and their potential in developing next-generation therapeutics for AD.